Field of Invention
The present invention relates to a novel economically and ecologically efficient process for preparing N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethan-1-amine from 2,2-difluoroethylamine and 2-chloro-5-(chloromethyl)pyridine (CCMP) in the presence of an inorganic base, wherein the inorganic base is selected from the group consisting of alkali metal hydroxides and alkaline earth metal hydroxides.
Description of Related Art
N-[(6-Chloropyridin-3-yl)methyl]-2,2-difluoroethan-1-amine is an important intermediate in the preparation of agrochemical active ingredients (see WO-A-2007/115644). Various processes for preparing N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethan-1-amine have been described. However, the existing processes have various disadvantages as described below.
For example, WO-A-2009/036900 discloses a process for preparing N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethan-1-amine by amide hydrogenation of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroacetamide (scheme 1).

The disadvantage of this process is that it employs complex and very costly hydrides such as sodium borohydride which require highly elaborate safety measures.
WO 2009/036901 describes the reduction of N-(6-chloropyridin-3-yl)methylene-2,2-difluoroethanamine with hydrogen (scheme 2).

The disadvantage of this process is that it employs hydrogen, since here too the use of hydrogen requires highly elaborate safety measures.
WO-A-2011/157650 describes the preparation of 2,2-difluoroethanamine derivatives from 2,2-difluoro-1-haloethanes and primary amines in the presence of organic bases (scheme 3).

The disadvantage of this process is that the reaction needs to be carried out in a high-pressure apparatus.
Patent publication WO-A-2007/115644, concerning the preparation of insecticidally active 4-aminobut-2-enolide compounds, describes the preparation of compounds of general formula A—CH2—NH—R1, where A represents specific heterocycles and R1 represents haloalkyl, by alkylation of the nitrogen (scheme 4).

E=hal, for example chlorine, bromine, iodine; O-tosyl, O-mesyl,
Specifically, WO-A-2007/115644 describes the preparation of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethan-1-amine (compound (3)) which is synthesized from CCMP (compound (2)) and 2,2-difluoroethan-1-amine (compound 1)) in the presence of triethylamine (see scheme 5). Compounds (1), (2) and triethylamine are employed in equimolar amounts. The desired product is obtained in a yield of 53%.

The process described in WO-A-2007/116544 for preparing compounds of formula A—CH2—NH—R1, where A represents specific heterocycles and R1 represents haloalkyl, is disadvantageous since polyalkylation of the nitrogen may occur during the reaction. This leads to yield loss which is also apparent in the yield of the specifically cited example. The yield was only 53%. These polyalkylations can be reduced only by using a large excess of amine However, the distillative recovery of the costly amine is generally laborious and leads to losses.
WO-A-2014/001245 describes a process for preparing N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethan-1-amine in the presence of N,N-diisopropylethylamine (Hünig's base). However, WO-A-2014/001245 does not disclose carrying out the reaction in the presence of an inorganic base such as NaOH for example.
Hünig's base is a very costly base which is difficult to obtain on a large industrial scale and which is employed in equimolar amounts in the process according to WO-A-2014/001245. Following the reaction, the base is present in the aqueous phase in the form of the amine hydrochloride. In order to recover the free base it is necessary to admix the aqueous phase with an inorganic base, separate the phases and subject the organic phase to a distillative work-up. The distillative recovery of the valuable Hünig's base is generally laborious and leads to losses. The aqueous phase moreover likewise comprises the Hünig's base, namely in typical concentrations of about 1 wt % as free Hünig's base. This leads to further losses. The free Hünig's base moreover contaminates the wastewater and the wastewater thus requires additional aftertreatment.
However, due to the significance of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethan-1-amine as a building block in the synthesis of agrochemical active ingredients it is necessary to find a process which can be employed economically and on a large industrial scale. It is also desirable to obtain N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethan-1-amine in high yield and purity, so that the target compound preferably need not be subjected to any further—potentially complex—purification.